Glial Cells and Polyamine Signaling in the Central Nervous System

中枢神经系统中的胶质细胞和多胺信号传导

• 批准号: 10351492
• 负责人: SERGUEI N SKATCHKOV
• 金额: $ 15.47万
• 依托单位: UNIVERSIDAD CENTRAL DEL CARIBE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10351492
• 关键词: Address; Adult; Aging; Alzheimer' s Disease; Animal Model; Astrocytes; Attention; Brain; Brain Diseases; Brain Injuries; Central Nervous System Diseases; Connexin 43; Development; Diagnosis; Disease; Elements; Epilepsy; Foundations; Future; Gap Junctions; Giant Cells; HIV-associated neurocognitive disorder; Human; Huntington Disease; Ischemia; Knowledge; Longevity; Measures; Metabolic Diseases; Morbidity - disease rate; Nerve Degeneration; Neuraxis; Neuroglia; Neurons; Parkinson Disease; Pathologic; Pathology; Pathway interactions; Physiological; Physiology; Polyamines; Prevention; Process; Public Health; Publications; Research; Retina; Risk; Role; SeSAME syndrome; Signal Transduction; Slice; Source; Spermidine; Spermine; Syndrome; Techniques; Testing; Therapeutic; Transgenic Animals; Trauma; Work; extracellular; graduate student; mortality; neglect; neurocognitive disorder; neuroprotection; neurotoxicity; novel; parent grant; uptake

Project Summary/Abstract (from Parent grant): Emerging recent publications show that polyamines (PAs) are key players in the exceedingly common disorders of aging and HIV associated neurocognitive disorders (HAND), Alzheimer's, Huntington's and Parkinson diseases as well as in Snyder-Robinson and SeSAME/EAST syndromes. PAs are released in whole brain from unknown sources during neuronal activity and trauma. PAs demonstrate neuroprotection against neurotoxicity, ischemia, brain injury and also increase longevity. Since PA content declines with aging or during pathology, the neuroprotection afforded by PAs can decline as well. This substantially increases the risk of morbidity and mortality. Despite its public health importance, relatively little is known about PA fluxes in brain and insufficient attention is paid to glial cells in CNS. Intriguingly, we found that in healthy adult brain and retina, glial cells but not neurons accumulate preferentially PAs such as spermidine (SD) and spermine (SP). We further recently found that PAs are the major openers of astrocytic connexin-43 (Cx43) gap junctions (GJs). Therefore, since Cx43 GJs are the major communicating channels between astrocytes, PAs keep glial syncytium integrity that may help to hold healthy brain status, however in many (patho)physiological conditions the situations are not well studied. The storage of internal PAs and their effects regulated by glia on brain function are some of the remaining mysteries and our findings raise key questions: (i) What are the mechanisms that underlie such uneven distribution and accumulation of PAs between astrocytes and neurons? (ii) What are the mechanisms of PA release in CNS from glia? (iii) What are the consequences of PA fluxes within the brain on neuronal function? and (iv) Ultimately, what are the roles of PAs in brain disorders and diseases? The glial PA pathways hitherto have been neglected, although it is evident that these molecules are key elements for normal brain status and their metabolic disorders, apparently, cause the development of many pathological syndromes and diseases. We have developed techniques for measuring PA fluxes in brain slices and retina and will use transgenic animal models of HAND (and in the future of other diseases) to study (patho)physiology of PA translocation. In this project, we will test the original hypothesis that PAs are novel “gliotransmitters” that (i) are transported into glia, (ii) open astrocytic intercellular gap junctions, (iii) propagate in the astrocyte-to-astrocyte syncytium (AIM-1) and (iv) are released from glia upon local stimulation (v) to regulate the neuronal-glial network (AIM-2). We will address these two aims to determine mechanisms of PA uptake/accumulation/release/signaling in CNS. The studies will lead to new scientific knowledge and research opportunities for graduate students to further understand neurodegenerative processes, helping advance diagnosis, treatment and prevention.

项目摘要/摘要（来自家长资助）： 最近出现的出版物表明，多胺 (PA) 是极其常见的问题的关键参与者。 衰老障碍和 HIV 相关神经认知障碍 (HAND)、阿尔茨海默病、亨廷顿舞蹈症和 帕金森病以及 Snyder-Robinson 综合征和 SeSAME/EAST 综合征。 PA已全部发布 在神经元活动和创伤期间来自未知来源的大脑。 PA 表现出神经保护作用 神经毒性、缺血、脑损伤，还能延长寿命。由于 PA 含量会随着老化或在 病理学上，PA 提供的神经保护作用也会下降。这大大增加了风险 发病率和死亡率。尽管它对公共卫生很重要，但人们对大脑中 PA 通量的了解相对较少 对中枢神经系统中的胶质细胞关注不够。 有趣的是，我们发现在健康成人的大脑和视网膜中，神经胶质细胞而不是神经元积聚 优选PA，例如亚精胺(SD)和精胺(SP)。我们最近进一步发现 PA 是 星形细胞连接蛋白 43 (Cx43) 间隙连接 (GJ) 的主要开启者。因此，由于 Cx43 GJ 是主要的 星形胶质细胞之间的通讯通道，PAs 保持神经胶质合胞体的完整性，这可能有助于保持健康 然而，在许多（病理）生理条件下，这些情况尚未得到充分研究。 内部 PA 的储存及其受神经胶质细胞调节对大脑功能的影响是其中的一些因素 仍然存在的谜团和我们的发现提出了关键问题：（i）这种现象背后的机制是什么？ PA在星形胶质细胞和神经元之间的分布和积累不均匀？ (二) 机制是什么 CNS 中神经胶质细胞释放 PA 的量？ (iii) 脑内 PA 通量对神经元有何影响？ 功能？ (iv) 最终，PA 在大脑紊乱和疾病中发挥什么作用？ 尽管很明显这些分子是关键，但迄今为止，神经胶质 PA 途径一直被忽视 显然，正常大脑状态的要素及其代谢紊乱会导致许多疾病的发展 病理综合征和疾病。我们开发了测量脑切片 PA 通量的技术 和视网膜，并将使用 HAND 的转基因动物模型（以及未来的其他疾病）来研究 PA 易位的（病理）生理学。在这个项目中，我们将测试 PA 是新颖的原始假设 “胶质细胞递质”，(i) 被转运到神经胶质细胞中，(ii) 打开星形胶质细胞间间隙连接，(iii) 在星形胶质细胞间的合胞体 (AIM-1) 中传播，并且 (iv) 在局部刺激后从神经胶质细胞中释放 (v) 调节神经元-胶质网络 (AIM-2)。 我们将解决这两个目标，以确定 PA 吸收/积累/释放/信号传递的机制 中枢神经系统。这些研究将为研究生带来新的科学知识和研究机会 进一步了解神经退行性过程，有助于推进诊断、治疗和预防。